rs142120301

chr2-29717673-G-Achr2-29717673-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004304.5(ALK):c.692C>T(p.Thr231Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T231R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15562016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.692C>T	p.Thr231Ile	missense_variant	2/29	ENST00000389048.8
ALK	XR_001738688.3	n.1619C>T		non_coding_transcript_exon_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.692C>T	p.Thr231Ile	missense_variant	2/29	1	NM_004304.5	P1
ALK	ENST00000618119.4	c.-440C>T		5_prime_UTR_variant	1/28	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2023

The p.T231I variant (also known as c.692C>T), located in coding exon 2 of the ALK gene, results from a C to T substitution at nucleotide position 692. The threonine at codon 231 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.038
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.62	P
Vest4		0.23
MutPred		0.25		Loss of glycosylation at T231 (P = 0.002);
MVP		0.37
MPC		0.21
ClinPred		0.59	D
GERP RS		5.3
Varity_R		0.084
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142120301; hg19: chr2-29940539;